P006. The therapeutic potential of the pharmacological inhibition of PBEF/NAMPT/Visfatin in inflammatory bowel disease

Background

Crohn's disease (CD) and Ulcerative Colitis (UC) are the two major entities of human inflammatory bowel disease (IBD). Despite recent advances in our understanding of the underlying biological mechanisms of disease, current available therapies in some patients still remain insufficiently. In IBD patients, high circulating PBEF/NAMPT/Visfatin serum levels have been observed and elevated mRNA expression in inflamed mucosal tissue has been demonstrated. Inflammatory processes demand large amounts of energy in the form of energy-enriched substrates and enzymatic co-factors. PBEF/NAMPT/Visfatin has an important role in a central cellular energy pathway, catalyzing the rate-limiting step in the biosynthesis of NAD+ from nicotinamide. Thus PBEF/NAMPT/Visfatin could impact inflammatory pathways by modulating the synthesis and bioavailability of NAD in various cells. This study aims to investigate the activation state of PBEF/NAMPT/Visfatin and components of the “NAD salvage pathway” in IBD patients. Based on this data we study the potency of FK866, a specific inhibitor of PBEF/NAMPT/Visfatin.

Methods

We investigated the therapeutic effect of FK866 in an acute and chronic animal model of IBD. Acute colitis was induced by 3.5% Dextran Sulfate Sodium (DSS) in C57/Bl6 wildtype mice. The therapy group was administered 20 mg/kg FK866 daily compared to vehicle treated control mice. As a chronic model we used 13-week-old IL-10 knockout mice receiving either 20 mg/kg FK866 or saline daily for a total of 2 weeks. Clinical and histological features as well as proinflammatory cytokines were determined. NAD+ and its metabolite levels in epithelium are measured by HPLC/mass spectrometric methods.

Results

Animals treated with the small molecule inhibitor FK866 show a better clinical activity index, reduced histological inflammation and significantly lowered proinflammatory cytokine levels like TNFα, IL-6 and IL-1β in the colon. Il-6 levels in serum were significantly lower in the treatment group.

Conclusion

The administration of FK866 and the resulting depletion of intracellular NAD levels results in better clinical and histological outcomes and significantly lowers mRNA expression of various pro-inflammatory cytokines. Hence, FK866 in mice seems to be beneficial in terms of a novel therapeutic strategy. Preliminary data suggest that the measurement of NAD and its metabolites is sensitive regarding the prediction of treatment response. In the next step we will investigate the transmissibility of this concept in human IBD patients using a whole tissue culture approach. Hopefully, our data will pave the way to establish a new therapeutic concept for treating inflammatory conditions, especially IBD.